STAT3 mutation-associated airway epithelial defects in Job syndrome

Yihan Zhang, Tian Lin, Hui Min Leung, Cheng Zhang, Brittany Wilson-Mifsud, Michael B. Feldman, Anne Puel, Fanny Lanternier, Louis Jean Couderc, Francois Danion, Emilie Catherinot, Hélène Salvator, Colas Tcherkian, Claire Givel, Jie Xu, Guillermo J. Tearney, Jatin M. Vyas, Hu Li, Bryan P. Hurley, Hongmei Mou

Research output: Contribution to journalArticlepeer-review


Background: Job syndrome is a disease of autosomal dominant hyper-IgE syndrome (AD-HIES). Patients harboring STAT3 mutation are particularly prone to airway remodeling and airway infections. Objectives: Airway epithelial cells play a central role as the first line of defense against pathogenic infection and express high levels of STAT3. This study thus interrogates how AD-HIES STAT3 mutations impact the physiological functions of airway epithelial cells. Methods: This study created human airway basal cells expressing 4 common AD-HIES STAT3 mutants (R382W, V463del, V637M, and Y657S). In addition, primary airway epithelial cells were isolated from a patient with Job syndrome who was harboring a STAT3-S560del mutation and from mice harboring a STAT3-V463del mutation. Cell proliferation, differentiation, barrier function, bacterial elimination, and innate immune responses to pathogenic infection were quantitatively analyzed. Results: STAT3 mutations reduce STAT3 protein phosphorylation, nuclear translocation, transcription activity, and protein stability in airway basal cells. As a consequence, STAT3-mutated airway basal cells give rise to airway epithelial cells with abnormal cellular composition and loss of coordinated mucociliary clearance. Notably, AD-HIES STAT3 airway epithelial cells are defective in bacterial killing and fail to initiate vigorous proinflammatory responses and neutrophil transepithelial migration in response to an experimental model of Pseudomonas aeruginosa infection. Conclusions: AD-HIES STAT3 mutations confer numerous abnormalities to airway epithelial cells in cell differentiation and host innate immunity, emphasizing their involvement in the pathogenesis of lung complications in Job syndrome. Therefore, therapies must address the epithelial defects as well as the previously noted immune cell defects to alleviate chronic infections in patients with Job syndrome.

Original languageEnglish (US)
Pages (from-to)538-550
Number of pages13
JournalJournal of Allergy and Clinical Immunology
Issue number2
StatePublished - Aug 2023


  • AD-HIES STAT3 mutation
  • cell differentiation
  • innate immunity
  • mucociliary clearance
  • neutrophil chemotaxis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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